Novel quinolinepiperazinyl-aryltetrazoles targeting the blood stage of Plasmodium falciparum.

The emergence of drug resistance against the frontline antimalarials is a major challenge in the treatment of malaria. In view of emerging reports on drug-resistant strains of Plasmodium against artemisinin combination therapy, a dire need is felt for the discovery of novel compounds acting against novel targets in the parasite. In this study, we identified a novel series of quinolinepiperazinyl-aryltetrazoles (QPTs) targeting the blood stage of Plasmodium. In vitro anti-plasmodial activity screening revealed that most of the compounds showed IC50 < 10 µM against chloroquine-resistant PfINDO strain, with the most promising lead compounds 66 and 75 showing IC50 values of 2.25 and 1.79 µM, respectively. Further, compounds 64-66, 68, 75-77 and 84 were found to be selective (selectivity index >50) in their action against Pf over a mammalian cell line, with compounds 66 and 75 offering the highest selectivity indexes of 178 and 223, respectively. Explorations into the action of lead compounds 66 and 75 revealed their selective cidal activity towards trophozoites and schizonts. In a ring-stage survival assay, 75 showed cidal activity against the early rings of artemisinin-resistant PfCam3.1R539T. Further, 66 and 75 in combination with artemisinin and pyrimethamine showed additive to weak synergistic interactions. Of these two in vitro lead molecules, only 66 restricted rise in the percentage of parasitemia to about 10% in P. berghei-infected mice with a median survival time of 28 days as compared to the untreated control, which showed the percentage of parasitemia >30%, and a median survival of 20 days. Promising antimalarial activity, high selectivity, and additive interaction with artemisinin and pyrimethamine indicate the potential of these compounds to be further optimized chemically as future drug candidates against malaria.

Design, synthesis, biological evaluation and molecular dynamics of some novel 3-phenylpyrazolo[1,5-a]pyrimidine-2,7(1H,4H)-dione based compounds as anti-tubercular agents.

Decaprenylphosphoryl-ß-d-ribose-2'-epimerase (DprE1) is a druggable target which is being exploited for the development of new anti-TB agents. In the present work, we report developing a pharmacophore model and performing virtual screening of Asinex database using the developed pharmacophore model to get eight hits as potential DprE1 inhibitors. The hits were used as leads to design new 3-phenylpyrazolo[1,5-a]pyrimidine-2,7(1H,4H)-dione based potential anti-TB agents. On the basis of the identified lead molecules, a total of 18 compounds were synthesized and evaluated for their anti-TB activity by using MABA. ADMET predictions for all the compounds revealed that these compounds have drug-like and lead-like properties. One of the final compounds was found to exhibit potent anti-TB activity against Mycobacterium bovis.Communicated by Ramaswamy H. Sarma.

Overview of the Development of DprE1 Inhibitors for Combating the Menace of Tuberculosis.

Decaprenylphosphoryl-ß-d-ribose 2'-epimerase (DprE1), a vital enzyme for cell wall synthesis, plays a crucial role in the formation of lipoarabinomannan and arabinogalactan. It was first reported as a druggable target on the basis of inhibitors discovered in high throughput screening of a drug library. Since then, inhibitors with different types of chemical scaffolds have been reported for their activity against this enzyme. Formation of a covalent or noncovalent bond by the interacting ligand with the enzyme causes loss of its catalytic activity which ultimately leads to the death of the mycobacterium. This Perspective describes various DprE1 inhibitors as anti-TB agents reported to date.

Vicinal diaryl azole-based urea derivatives as potential cholesterol lowering agents acting through inhibition of SOAT enzymes.

A novel series of vicinal diaryl azole-urea derivatives were synthesized and evaluated for their potential to inhibit SOAT enzyme. Among the reported compounds, compound (12d) emerged as the most potent compound with an IC50 value of 2.43 µM. In polaxamer-407 induced lipoprotein lipase inhibition model, compound (12d) reduced triglyceride turnover in vivo. Compound (12d) also showed dose-dependent prevention of serum total cholesterol and prevention of LDL-C elevation at a dose of 30 mg/kg. Furthermore, compound (12d) showed potential to stop falling levels of serum HDL-C dose-dependently and improved the atherogenic index. Effect of 12d on body weight, plaque formation and development of atherogenic lesions were studied. Toxicological study of compound (12d) indicated that at a dose of 2000 mg/kg, 12d was devoid of any signs of toxicity or mortality.

Medicinal Chemistry Perspective of Fused Isoxazole Derivatives.

Nitrogen containing heterocyclic rings with an oxygen atom is considered as one of the best combination in medicinal chemistry due to their diversified biological activities. Isoxazole, a five membered heterocyclic azole ring is found in naturally occuring ibetonic acid along with some of the marketed drugs such as valdecoxib, flucloxacillin, cloxacillin, dicloxacillin, and danazol. It is also significant for showing antipsychotic activity in risperidone and anticonvulsant activity in zonisamide, the marketed drugs. This review article covers research articles reported till date covering biological activity along with SAR of fused isoxazole derivatives.

Developing steroidal aromatase inhibitors-an effective armament to win the battle against breast cancer.

Breast cancer, an emerging disease among the women population, occurs due to overexpression of estrogens. The enzyme aromatase plays a key rate limiting role in the biosynthesis of estrogens. Certain clinical advantages of the use of exemestane, a steroidal aromatase inhibitor over non-steroidal aromatase inhibitors have drawn the attention of researchers for the development of novel steroidal aromatase inhibitors.The current review is a humble attempt to compile the reports by various researchers till date on the synthesis of steroidal aromatase inhibitors. It has been tried to encompass the structural modifications carried out by various researchers in the steroid ring system by taking up the functional group modifications on rings A, B, ring A/B junction, ring-D, ring modifications, bridged derivatives and heterocyclic ring-fused derivatives in a systematic way.

A comprehensive patents review on cannabinoid 1 receptor antagonists as antiobesity agents.

INTRODUCTION: Obesity is a rapidly expanding worldwide health problem. Various targets are investigated presently for the treatment of obesity, but there remains an unmet need for an effective drug therapy with acceptable efficacy levels and reduced side effects. Targeting peripherally located cannabinoid 1 (CB1) receptors is an attractive strategy as these receptors play a vital role in energy homeostasis. AREAS COVERED: CB1 receptor antagonists constitute one of the most important categories of compounds of interest for the control of obesity. In this review, the authors focus on recent advances (since 2007) in diverse chemical classes of patented compounds belonging to the category of CB1 receptor antagonists. EXPERT OPINION: Safer CB1 receptor antagonists for the treatment of obesity can be discovered by developing such compounds that act peripherally. Increasing the polar service area, decreasing the lipophilicity and designing of neutral antagonists and allosteric inhibitors are some interesting strategies that could offer promising results.

Discovery of anti-malarial agents through application of in silico studies.

Among the various parasitic diseases, malaria is the deadliest one. Due to the emergence of high drug resistance to the existing drug candidates there is a global need for development of new drug candidates which will be effective against resistant strains of malaria parasite. In silico molecular modeling approaches have been playing an important role in the discovery of novel lead molecules having antimalarial activity. Present review is an effort to cover all the developments related to the application of computational techniques for the design and discovery of novel antimalarial compounds since the year 2011 onwards.

Unequivocal role of pyrazine ring in medicinally important compounds: a review.

Pyrazine is one of the important class of heterocyclic compounds that can be obtained naturally or synthesized chemically. Pyrazine ring has got importance in exhibiting various biological activities in association with other scaffolds like pyrrole, pyrazole, imidazole, triazole, tetrazole, thiophene, oxazole, pyridine, piperidine and piperazine. Presence of pyrazine ring as a basic scaffold in various clinically used drugs exhibits its importance in drug design. In this review, attempt has been made to disclose various therapeutic applications of pyrazine derivatives reported during the last decade.